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PubMed2006

The role of xenoestrogenic compounds in the development of breast cancer.

Lifetime exposure to endogenous steroidal estrogens is an established risk factor for breast cancer, and exposures to other estrogenic and antiestrogenic compounds might also modify the risk of breast cancer. It has been hypothesized that synthetic estrogenic industrial pollutants such as organochlorine compounds and plant-derived estrogenic compounds also modify breast cancer risks; however, recent studies show that levels of organochlorine pollutants are similar in breast cancer patients and controls. There is evidence that synthetic and plant-derived estrogens are selective estrogen receptor modulators, which implies that these compounds can induce tissue-specific, time- and dose-dependent estrogenic or antiestrogenic responses. Therefore, the effects of synthetic or plant-derived estrogens on the incidence of breast cancer depend on both the levels and the timing of exposure to these compounds, particularly during stages of mammary gland development that are extremely sensitive to hormone levels.

Breast Neoplasms↗
PubMed2003

Functional aspects of estrogen neuroprotection.

Evidence that estrogen protects neurons against toxic/ ischemic insults or degenerative/aging processes is evident in a variety of in vitro and in vivo systems. However, a critical remaining question is: Does the demonstrated morphologic and neurochemical protection by estrogen lead to a preservation of brain function or an enhanced ability to recover? To date, little basic research is available on this issue. Cognition is a critical function that might provide a sensitive way to examine this question. As a first step, we present results showing that two chronic environmental insults, psychoactive drugs and stress, produce gender-specific responses in cognitive abilities. Specifically, females appear less sensitive than males to cognitive impairments following chronic exposure to these factors. Results are presented in male and female rats utilizing cognitive tests that assess visual (object recognition) and spatial memory (object placement and radial arm maze) following chronic amphetamine, methamphetamine, or daily restraint stress. Following regimes of chronic stress or amphetamine, males were impaired on these tasks while females were either unaffected, less affected, or enhanced in performance. These observations suggest that differences in circulating gonadal hormone levels between the sexes may contribute to the differential sensitivity of the sexes and provide endogenous neuroprotection for females. Surprisingly, ovariectomized females were still not impaired following a stress regimen that impaired males (21 d of daily restraint). These data taken together with neurochemical data on estrogen neuroprotective effects indicate that it is possible that neuroprotection by estrogen may result from hormone action both during sexual differentiation (organizational effect) and in adulthood (activational effect). These considerations and possible unwanted/untoward effects of chronic estrogen use are discussed in relation to the use of selective estrogen receptor modulators for chronic treatment of both males and females. In conclusion, although compelling evidence for neuroprotection by estrogen has been presented in anatomic and neurochemical studies, it is clear that the functional/ behavioral aspects need further investigation.

Animals↗
PubMed2001

Induction of the progesterone receptor gene in estrogen target cells monitored by branched DNA signal amplification.

Estrogens have multiple effects on the growth and development of cells in their target tissues, including the uterus, ovary, breast, bone marrow and brain. The hormone regulates the transcription of diverse genes in these tissues via the estrogen receptor, a nuclear transcription factor. Naturally occurring estrogens and estrogen analogs including selective estrogen receptor modulators (SERMs), constitute important therapies for breast cancer and osteoporosis, and are major components of oral contraceptives. The in vitro biologic activities of pharmaceutical estrogen agonists and antagonists have frequently been monitored by cotransfection assay, where exogenous estrogen receptor and reporter genes are transiently inserted into a heterologous, non receptor-containing cell line, such as those derived from kidney cells. Here we describe an alternative to this method, where induction of an endogenous estrogen-responsive gene, the progesterone receptor gene, is monitored by branched DNA signal amplification. Assays are performed with cultured cells derived from estrogen-responsive tissues; namely, breast, uterine endothelium and bone. Hormonal induction occurs via the endogenous estrogen receptor of these cells. Our data show that SERMs, which are estrogen agonists on bone in vivo, antagonize estrogen-dependent target gene induction in conditionally immortalized osteoblast-like cells.

Alkaline Phosphatase↗
PubMed2003

Origin and characteristics of adverse events in aromatase inhibition therapy for breast cancer.

Estrogen is critical in the progression and probably also in the initiation of breast tumors. Two classes of pharmacologic agents currently used in the treatment of estrogen receptor-positive breast tumors are the selective estrogen receptor modulators such as tamoxifen that block the interaction of estrogen with its cognate receptor, and the aromatase inhibitors (AIs) that block the final enzymatic step in the estrogen biosynthetic pathway. Recent data from first-line phase III trials in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer suggest that AIs are at least equivalent to or more effective than tamoxifen in this setting. As a result AIs are being evaluated in the adjuvant setting and may eventually displace tamoxifen as the endocrine therapy of choice for postmenopausal patients with breast cancer. Among the side effects of therapy that were observed in metastatic trials, AIs have shown less vascular and uterine adverse events than tamoxifen. Some concern exists, however, regarding their effect on lipid metabolism and bone turnover. To be acceptable for adjuvant treatment, AIs will have to show not only an advantage in efficacy, but also that any concerns from potential side effects may be managed appropriately. This article reviews the safety profile of AIs, discussing events related to their chemical structure, their specificity, and the effects of estrogen deprivation on target organs.

Antineoplastic Agents, Hormonal↗
PubMed2002

Raloxifene- and estradiol-mediated effects on uterus, bone and B lymphocytes in mice.

Raloxifene is a selective estrogen receptor modulator approved for the prevention of osteoporosis in postmenopausal women. It is selective by having estrogen-agonistic effects on bone, vessels and blood lipids while it is antagonistic on mammary and uterine tissue. Our aim was to study the agonistic and antagonistic properties of the raloxifene analogue LY117018 (LY) on uterus, bone, B lymphopoiesis and B cell function. Oophorectomized and sham-operated animals were treated with s.c. injections of equipotent anti-osteoporotic doses of 17beta-estradiol (E2) (0.1 mg/kg) or LY (3 mg/kg) or vehicle as controls. Effects on bone mineral density (BMD) were studied using peripheral quantitative computed tomography, uterine weight was examined, B lymphopoiesis was examined using flow cytometry and B cell function in bone marrow and spleen was studied by the use of an ELISPOT assay. E2 and LY had similar effects on BMD and bone marrow B lymphopoiesis, while LY had a clear antagonistic effect on endogenous estrogen in uterine tissue and no stimulating effect on the frequency of Ig-producing B cells in sham-operated animals. Our results are discussed in the context of estrogen receptor biology, relations between the immune system and bone metabolism and also with respect to the estrogen-mediated effects on rheumatic diseases.

Animals↗
PubMed2002

Vasomotor and vascular effects of hormone replacement therapy.

Cardiovascular risk factors impair endothelium-dependent vasodilation as well as other functions of the endothelium, thereby predisposing the patient to atherosclerosis and its overt clinical manifestations. Loss of endogenous estrogen also leads to reduced bioavailability of endothelium-derived nitric oxide. In premenopausal women, the impairment of endothelial function develops within 1 month of surgical ovariectomy and is reversed by the administration of exogenous 17 beta-estradiol. Exogenous estrogen administration restores endothelial function by enhancing nitric oxide synthesis through genomic and nongenomic mechanisms and by reducing oxidative stress and nitric oxide breakdown. The effect of progesterone on endothelial function is still under investigation. In animal studies, medroxyprogesterone acetate (MPA) counteracts estrogen's beneficial effects on endothelial function and on coronary plaque size. In humans, however, the addition of progesterone to estradiol does not appreciably attenuate estrogen-associated endothelium-dependent vasodilation. Secondary prevention trials with conjugated equine estrogen plus MPA have no proven benefit in reducing coronary events, progression of angiographic coronary atherosclerosis, or incidence of cerebrovascular events. This suggests that beneficial effects of estrogen on endothelial function are counterbalanced by detrimental effects, perhaps because of proinflammatory and prothrombotic actions. The selective estrogen receptor modulators are currently under investigation as agents that might retain the favorable, without possessing the unfavorable, effects of estrogen on the vascular system.

Animals↗
PubMed2003

In vitro effects of the Cimicifuga racemosa extract BNO 1055.

OBJECTIVES: Extracts of Black cohosh (Cimicifuga racemosa or CR) have been used for the treatment of climacteric complaints since decades. Efficacy, particularly concerning neurovegetative and psychic symptoms, has been proven in clinical trials. As active principle yet unknown substances with selective estrogen receptor modulator (SERM) activity are assumed. Recently, evidence arose that CR may also contain dopaminergic compounds, which may contribute to the therapeutic activity of the extract. METHODS: Two subtypes of the estrogen receptor (ERalpha and ERbeta) are known. To examine, whether active substances of CR extract BNO 1055 (which is contained in Klimadynon and Menofem) bind to either of the two estrogen receptors, subtype-specific estrogen receptor ligand-binding assays with recombinant ERalpha or ERbeta were conducted. A ligand-binding assay with recombinant dopamine D(2)-receptor protein was employed to assess possible dopaminergic activity in the CR extract BNO 1055. RESULTS: While a displacement of radiolabeled estradiol from binding sites of a cytosol preparation from procine and human endometrium by CR extract BNO 1055 was shown no such displacement was achieved when either ERalpha or ERbeta protein was used as ligands for tracer. Dopaminergic activity in the CR extract BNO 1055 could be demonstrated with the D(2)-receptor assay. A countercurrent chromatography resulted in a separation of estrogenic and dopaminergic activity in two distinct fractions. CONCLUSIONS: It is suggested that not yet identified substances in the CR extract BNO 1055 bind to a yet unknown estrogen-binding site in the endometrium. Also, yet unknown dopaminergic compounds may contribute to the pharmacological profile of CR extract BNO 1055.

Cimicifuga↗
PubMed2002

[Estrogen receptor subtypes and the regulatory effect of receptor ligand binding on gene transcription].

This review introduces the structure, functions, tissue distribution, physiologic roles of estrogen receptor subtypes (ER alpha and ER beta) along with transcriptional activities of estrogen receptor ligands and the mechanism of the modulatory pathway and tissue specific property of selective estrogen receptor modulators (SERMs), and phytoestrogens. This article is to provide a systemic approach for increasing the selectivity of estrogenic drug and optimizing the clinically based strategy of drug design. Differences exist between ER alpha and ER beta in structure, function, tissue distribution, physiologic roles and response to ligands, as well as the regulating effect on gene transcription, which are mainly determined by different co-regulators they recruit respectively.

Animals↗
PubMed2001

Evidence for an estrogen-like action of raloxifene upon the hypothalamic-pituitary unit: raloxifene inhibits luteinizing hormone secretion and stimulates prolactin secretion in ovariectomized female rats.

Selective estrogen receptor modulators (SERMs) constitute a new family of drugs with growing interest in the management of estrogen-associated pathology. Raloxifene is a SERM that is used to treat and prevent osteoporosis in postmenopausal women. The actions of raloxifene on bone, breast, uterus and serum cholesterol have been widely analyzed, but very few studies have been carried out to evaluate whether raloxifene has an estrogenic activity upon the hypothalamic-pituitary axis in the rat. For this purpose, adult female rats were ovariectomized or sham ovariectomized. One week later, the rats were implanted with intracardiac canullae and 24 h after injected daily with raloxifene (500 microg/rat/day) or vehicle for 5 days. One hour after the last injection, blood samples were obtained at 5 min intervals for a 3 h. period (10:00-13:00 h). Our results indicate that raloxifene inhibits the pulsatile nature of the post-ovariectomy hypersecretion of luteinizing hormone (LH) and increases prolactin (PRL) secretion in ovariectomized animals. These effects are suggestive of an estrogenic activity of raloxifene on LH and PRL secretion in ovariectomized females.

Animals↗
PubMed2002

Osteoporosis: a review and its dental implications.

Osteoporosis is a disease that affects primarily women, but can also occur in men. It is characterized by a loss of bone mineral density (BMD), and often culminates in a fracture of the hip, wrist, and/or vertebrae. The diagnosis of osteoporosis is often made by using bone density measurements. They are often expressed in relative terms (T-scores and Z-scores); the Z-score is the number of standard deviations from the age-matched average value of healthy women. A low Z-score indicates the bone density is lower than it should be for a patient's age and sex. Osteoporosis is defined as a BMD loss of 2.5 standard deviations or more below the established mean. Osteoporosis can be treated by a variety of methods, the most common being the use of estrogen, with or without progestin or progesterone. The use of estrogen alone is referred to as estrogen replacement therapy (ERT), and the combination hormone replacement therapy (HRT). Other drugs used in the treatment of osteoporosis are the selective estrogen receptor modulators (SERMs) and the bisphosphonates. The SERMs appear to offer many of the positive benefits of estrogen with fewer adverse effects on the breast or uterus. Recently, a randomized, double blind study of nearly 3,000 women found no overall benefit in reducing heart disease for those taking estrogen. In fact, in the first year of estrogen use, heart disease was higher in this group than in those taking placebo. The relationship between systemic BMD and periodontal status has been investigated. In some patients, there is a correlation between a decrease of mandibular bone mass and tooth loss. In others, there is no such correlation. Those postmenopausal women taking HRT had greater tooth retention and a reduced likelihood of edentulism. A recent study has found no correlation between clinical attachment levels and the BMD of the lumbar spine. Many possible factors contribute to the development of osteoporosis and periodontal diseases. It is difficult to establish a direct correlation between tooth loss, bone loss, and loss of attachment resulting from periodontitis and decreased BMD associated with osteoporosis, but studies are ongoing.

Aged↗
PubMed2006

Estrogen-signaling pathway: a link between breast cancer and melatonin oncostatic actions.

BACKGROUND: Melatonin exerts oncostatic effects on different kinds of tumors, especially on endocrine-responsive breast cancer. The most common conclusion is that melatonin reduces the incidence and growth of chemically induced mammary tumors, in vivo, and inhibits the proliferation and metastatic behavior of human breast cancer cells, in vitro. Both studies support the hypothesis that melatonin oncostatic actions on hormone-dependent mammary tumors are mainly based on its anti-estrogenic actions. METHODS AND RESULTS: Two different mechanisms have been proposed to explain how melatonin reduces the development of breast cancer throughout its interactions with the estrogen-signaling pathways: (a) the indirect neuroendocrine mechanism which includes the melatonin down-regulation of the hypothalamic-pituitary reproductive axis and the consequent reduction of circulating levels of gonadal estrogens and (b) direct melatonin actions at tumor cell level. Melatonin's direct effect on mammary tumor cells is that it interferes with the activation of the estrogen receptor, thus behaving as a selective estrogen receptor modulator. Melatonin also regulates the activity of the aromatases, the enzymes responsible for the local synthesis of estrogens, thus behaving as a selective estrogen enzyme modulator. CONCLUSIONS: The same molecule has both properties to selectively neutralize the effects of estrogens on the breast and the local biosynthesis of estrogens from androgens, one of the main objectives of recent antitumor pharmacological therapeutic strategies. It is these action mechanisms that collectively make melatonin an interesting anticancer drug in the prevention and treatment of estrogen-dependent tumors, since it has the advantage of acting at different levels of the estrogen-signaling pathways.

Animals↗
PubMed2004

Raloxifene relaxes rat cerebral arteries in vitro and inhibits L-type voltage-sensitive Ca2+ channels.

BACKGROUND AND PURPOSE: Because of their mixed estrogen-agonist and estrogen-antagonist properties, selective estrogen receptor modulators (SERMs) are considered promising substitutes for hormone replacement therapy. Raloxifene and other SERMs confer estrogen-like cardiovascular protective effects but lack the carcinogenic activity of exogenous estrogen. However, little is known about the cerebrovascular action of raloxifene. Therefore, we studied the effects of raloxifene on the mechanisms regulating rat cerebral artery tone. METHODS: Ring segments of the isolated rat posterior communicating cerebral arteries were mounted in a microvessel myograph for measurement of isometric tension. Whole-cell L-type voltage-sensitive Ca2+ currents were recorded using the perforated patch-clamp technique. Raloxifene (0.1 to 10 micromol/L) reduced the contractile responses to U46619, phenylephrine, and endothelin-1 in normal Krebs solution or to CaCl2 in Ca2+-free, high K+-containing solution. Raloxifene-induced relaxation was identical in endothelium-intact and endothelium-denuded rings. ICI 182780 had no effect on raloxifene-induced relaxation. Raloxifene reduced L-type Ca2+ currents with a pD2 of 5.98+/-0.06, close to that (6.44+/-0.09) for raloxifene-induced relaxation of 60 mmol/L K+-contracted rings. CONCLUSIONS: This study demonstrates that raloxifene acutely relaxes rat cerebral arteries largely via an endothelium-independent mechanism, involving inhibition of Ca2+ influx through L-type Ca2+ channels.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2006

Estrogenic agonist activity of ICI 182,780 (Faslodex) in hippocampal neurons: implications for basic science understanding of estrogen signaling and development of estrogen modulators with a dual therapeutic profile.

The present study sought to determine the characteristics of ICI 182,780 (Faslodex) action in rat primary hippocampal neurons. We first investigated the neuroprotective efficacy of ICI 182,780 against neurodegenerative insults associated with Alzheimer's disease and related disorders. Dose-response analyses revealed that ICI 182,780, in a concentration-dependent manner, significantly promoted neuron survival following exposure to either excitotoxic glutamate (200 muM)- or beta-amyloid(1-42) (1.5 muM)-induced neurodegeneration of hippocampal neurons. At a clinically relevant concentration of 50 ng/ml, ICI 182,780 exerted nearly maximal neuroprotection against both insults with efficacy comparable with that induced by the endogenous estrogen 17beta-estradiol. Thereafter, we investigated the impact of 50 ng/ml ICI 182,780 on mechanisms of 17beta-estradiol-inducible neuronal plasticity and neuroprotection. Results of these analyses demonstrated that ICI 182,780 directly induced a series of rapid intracellular Ca(2+) concentration ([Ca(2+)](i)) oscillations in a pattern comparable with that of 17beta-estradiol. In addition, ICI 182,780 exerted dual regulation of the glutamate-induced rise in [Ca(2+)](i) identical to that induced by 17beta-estradiol. Further analyses demonstrated that ICI 182,780 induced significant activation of extracellular signal-regulated kinase 1/2 and Akt (protein kinase B) and significantly increased expression of spinophilin and Bcl-2, with efficacy comparable with neurons treated with 17beta-estradiol. Taken together, results of these in vitro analyses of ICI 182,780 provide direct evidence of an estrogenic agonist profile of ICI 182,780 action in rat hippocampal neurons. Therapeutic development of neuroselective estrogen receptor modulators that mimic ICI 182,780 is discussed with respect to the potential of safe and efficacious alternatives to estrogen therapy for the prevention of postmenopausal cognitive decline and late-onset Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed2004

Raloxifene modulates interleukin-6 and tumor necrosis factor-alpha synthesis in vivo: results from a pilot clinical study.

Raloxifene (RAL), a selective estrogen receptor modulator, is indicated for the prevention and treatment of postmenopausal osteoporosis. RAL, by decreasing bone turnover, prevents bone loss and microarchitecture damage, reducing the incidence of osteoporotic fractures. Our previous in vitro data demonstrated that RAL modulates osteoclast activity by, at least in part, an IL-6- and TNF-alpha-dependent mechanism. In this study we evaluated the effects of RAL treatment (60 mg/d) on circulating levels of these cytokines in 14 postmenopausal women with osteoporosis. Lumbar bone density (determined by dual energy x-ray absorptiometry) and IL-6 and TNF-alpha levels were measured before and after 6 and 24 months of therapy. After 24 months, RAL increased bone density. IL-6 and TNF-alpha expression, elevated before treatment, significantly decreased (50% and 30%, respectively) after 6 months. This effect was sustained up to the end of the treatment (75% and 35%, respectively). Thus, our data show that RAL can modulate circulating levels of cytokines involved in osteoclastogenesis and bone resorption, suggesting that modulation of soluble factors could play a pivotal role in the mechanisms of the osteoprotective effect of RAL.

Bone Density↗
PubMed2002

[Hormone replacement therapy and its derivatives in the prevention and treatment of osteoporosis].

Hormone replacement therapy (HRT) is an established approach for the treatment and the prevention of osteoporosis. Many studies with bone mineral density as primary outcome have shown significant efficacy. Observational studies have indicated a significant reduction of hip fracture risk in cohorts of women who maintained HRT therapy. The Women's Health Initiative is the first prospective randomised controlled study which showed a positive effect of HRT in terms of reduction of vertebral and hip fractures risk. Unfortunately, this study has been interrupted after 5.2 years because of the unsupportable increase of risk of cardiovascular disease and breast cancer. Compliance with HRT, however, is typically poor because of the potential side effects and possible increased risk of breast or endometrial cancer. Nevertheless, there is now evidence that lower doses of estrogens in elderly women may prevent bone loss while minimizing the side effects seen with higher doses. Combination therapies using low doses estrogen should probably be reserved for patients who continue to fracture on single therapy. Selective estrogen receptor modulators (SERMs) are very interesting drugs. The goal of these agents is to maximize the beneficial effect of estrogen on bone and to minimize or antagonize the deleterious effects on the breast and endometrium. Raloxifene, approved for the prevention and the treatment of osteoporosis, has been shown to reduce the risks of vertebral fracture in large clinical trials. However, they don't reduce non vertebral fractures. Tibolone is a synthetic steroid that increased bone mineral density at lumbar spine and femoral neck. But no trial has been performed with fractures as end point.

Aged↗
PubMed2004

[Raloxifene and breast: from the SERMs concept to its place in clinical practice].

Raloxifene is a second generation Selective Estrogen Receptor Modulator. It is indicated in prevention and treatment of post-menopausal osteoporosis. This drug has an estrogen agonistic effect on bone tissue, an estrogen-antagonistic effect in breast and endometrial tissue. It inhibits estrogen induced breast cells proliferation and, in animal studies, it prevents the growth of chemically induced mammary tumors. Raloxifene has a limited effectiveness in women with advanced breast cancers. The effects of raloxifene after treated breast cancer and sequential use of tamoxifene after raloxifene (or the contrary) are not known and should be tested in specific pre-clinical and clinical studies. In osteoporotic women included in the MORE trial, the risk reduction of hormone-dependent breast cancer due to raloxifene raises the issue of some effectiveness of raloxifene in breast cancer prevention. The STAR trial is currently comparing tamoxifene vs raloxifene in breast cancer prevention in women at increased risk of breast cancer. Like tamoxifene, raloxifene increases the risk of venous thrombo-embolic events. On the other hand, in a subgroup of women at increased vascular risk in the MORE trial, the reduction of cardiovascular events raises the issue of an effect of raloxifene in the prevention of coronary events. The ongoing RUTH trial is testing this assumption and it is comparing raloxifene to a placebo in women at increased vascular risk. Today, in clinical practice, before the results of ongoing trail, raloxifene should be used in the setting of osteoporosis prevention and treatment.

Aged↗
PubMed2004

Hormones and breast cancer.

The incidence of breast cancer in women varies with age, mammary gland mass and exposure to endogenous and exogenous hormones. Age is the single most important factor and if, as projected, 32% of women will be aged >60 years by 2050, world breast cancer incidence will exceed the current 10(6) per year. Hormonal influences that affect growth of the mammary gland increase the risk of breast cancer; for example earlier menarche and later menopause. Childbearing protects against later development of breast cancer, and breastfeeding further decreases the risk. The breast cancer risk declines more with increasing total duration of breastfeeding. Exposure to hormonal contraceptives has been evaluated in a combined reanalysis of data from 51 epidemiological studies. There is a small transient increase in the relative risk of breast cancer among users of oral contraceptives but, since use typically occurs at young ages when breast cancer is relatively rare, such an increase would have little effect on overall incidence rates. In contrast, exposure to menopause hormone treatment occurs when the baseline risk of breast cancer is higher, and epidemiological studies and randomized controlled trials consistently find an increase in breast cancer risk with exposure to combined estrogen and progestogen. Women with a family history of breast cancer in first degree relatives have an increased risk of breast cancer but there is no evidence to suggest that this differs according to a woman's use of oral contraceptives or menopause hormone treatment. Selective estrogen receptor modulators are useful in the treatment and/or prevention of breast cancer depending on the specific agonist or antagonist effects on estrogen target tissues.

Age Factors↗